Process for the Preparation of Thiazolopyrimidines

ABSTRACT

A method for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; from a compound of the formula: (IV); wherein L represents a leaving group.

METHODS

The present invention relates to methods for preparingthiazolopyrimidine compounds, intermediate compounds used in suchmethods, thiazolopyrimidine compounds so prepared and their use intherapy.

In our published PCT patent application WO-01/25242 we describepharmaceutically active compounds of the general formula I

and pharmaceutically acceptable salts and solvates thereof, and methodsfor their preparation. Such methods include treatment of a compound offormula

where L is a leaving group such as chlorine, with an amine HNR²R³.

We have now devised an advantageous process for preparing compounds ofthe formula I. This novel process involves protection of the thiazolenitrogen atom and gives an improved yield of final product when comparedwith the prior art method described in WO-01/25242. By way of examplefor a compound of the above formula we have achieved displacement of achlorine leaving group by a group NR²R³ and subsequent conversion of the2-amino group to a carbonyl group, with about 40% overall yield. Incontrast we have achieved about 70% overall yield for the same productstarting from a compound of formula IV as set out hereinafter andwherein the leaving group L is chlorine.

Therefore in a first aspect of the invention we provide a method for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof:

in whichR¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, each of the groups being optionally substituted by one ormore substituent groups independently selected from halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹or an aryl or heteroaryl group, both of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethylgroups;R² and R³ each independently represent a hydrogen atom, or a C₃-C₇carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl group, thelatter four groups may be optionally substituted by one or moresubstituent groups independently selected from:(a) halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,—SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;(b) a 3-8 membered ring optionally containing one or more atoms selectedfrom O, S, NR⁸ and itself optionally substituted by C₁-C₃-alkyl orhalogen; or(c) an aryl group or heteroaryl group each of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹,—SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and trifluoromethyl groups;R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl group the latter two ofwhich may be optionally substituted by one or more substituent groupsindependently selected from halogen atoms, phenyl, —OR¹¹ and —NR¹²R¹³.

R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆ alkyl orphenyl group the latter two of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶—SONR¹⁵R¹⁶,NR¹⁵SO₂R¹⁶

or

R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocyclic ring system optionallycontaining a further heteroatom selected from oxygen and nitrogen atoms,which ring system may be optionally substituted by one or moresubstituent groups independently selected from phenyl, —OR¹⁴, —COOR¹⁴,—NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl,itself optionally substituted by one or more substituents independentlyselected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;

R¹⁰ represents a hydrogen atom or a C₁-C₆-alkyl or a phenyl group, thelatter two of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁷ and —NR¹⁵R¹⁶; and

each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ independentlyrepresents a hydrogen atom or a C₁-C₆ alkyl, or a phenyl group;

which method comprises contacting

wherein L is a leaving groupwith a thiazole nitrogen protecting group reagent under appropriatereaction conditions to form a compound of the formula

wherein PG is a protecting group,reacting the compound of formula III with an amine of formula HNR²R³ toform a compound of formula

and deprotection of the compound of formula II to give a compound of theformula I, and simultaneous or sequential conversion to apharmaceutically acceptable salt or solvate thereof.

Convenient leaving groups will be apparent to the chemist of ordinaryskill, such as disclosed in ‘Advanced Organic Chemistry’, 4^(th),edition, J. March, Wiley-Interscience (1992). Such groups will includehalogen atoms such as chlorine or bromine. Chlorine is a preferredleaving group for use in the invention.

Additional protection may be provided for the amine of formula HNR²R³for example where R² and/or R³ comprises a hydroxy or amino group. Byway of non-limiting example we refer to Example 3(d) where a particulardiol is introduced and protected via the compound(2,2,5-trimethyl-1,3-dioxan-5-yl)amine.

Convenient protecting groups will be apparent to the chemist of ordinaryskill. It will be appreciated that the more stable the resulting productupon protection the likelihood of increased difficulty in removing theprotecting group afterwards. Additionally, some resulting products uponprotection may not be sufficiently stable to isolation by standardlaboratory methods. The protection and deprotection of functional groupsis fully described in ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

Examples of suitable protecting groups for the given transformations, toprovide compounds of formula I, involving removal under appropriatehydrolytic conditions are [with suitable protecting group agentsindicated in square brackets] methoxymethyl [chloromethyl methyl ether],and particularly ethoxymethyl [chloromethyl ethyl ether ordiethoxymethane], benzyloxymethyl [benzyl chloromethyl ether],pivaloyloxymethyl [chloromethyl pivalate],2-(trimethylsilyl)ethoxymethyl [2-(trimethylsilyl)ethoxymethylchloride], 1-(ethoxy)ethyl [ethyl vinyl ether] and 2-tetrahydropyranyl[3,4-dihydro-(2H)-pyran]. Each individual protecting group listed aboveand its use represents a particular independent aspect of the invention.Base-assisted removal of the 2-(phenylsulfonyl)ethyl [phenyl vinylsulfone] protecting group under non-aqueous conditions is a suitablemethod for achieving these transformations.

The approach is also suited to catalytic reduction methods for removalof appropriate protecting groups. Such protecting groups include benzyl,diphenylmethyl, triphenylmethyl and benzyloxymethyl. Allyl as aprotecting group can be removed under metal-assisted conditions and4-methoxybenzyl, 2,4-dimethoxybenzyl and di(4-methoxyphenyl)methyl canbe removed under oxidative conditions. Acyl, benzoyl, pyrrolidinylmethyland urea-type protecting groups are other examples that can be removedunder appropriate hydrolytic conditions. Representative chloroformatereagents do not yield a carbamate protecting group, for example abenzylchloroformate reagent is found to yield a benzyl protecting group.

In the context of the present specification, unless otherwise indicated,an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituentgroup may be linear or branched. Aryl groups include phenyl andnaphthyl. Heteroaryl groups include 5- or 6-membered aromatic ringscontaining one or more heteroatoms selected from N, S, and O. Examplesinclude pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole,furan.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the methods of theinvention may be used with all geometric and optical isomers of thecompounds of formula (I) and mixtures thereof including racemates. Thescientist of ordinary skill will be able to select appropriateintermediate compounds to introduce the appropriate stereochemistry for—NR²R³ and R¹ (if appropriate).

Particular compounds of formula (I) are those in which R¹ represents anoptionally substituted benzyl group. More particularly R¹ representsbenzyl or benzyl substituted by one or more C₁-C₆ alkyl, C₁-C₆ alkoxy orhalogen atoms.

When R² and R³ represent a group substituted by one or more 3-8 memberedrings optionally containing one or more atoms selected from O, S or NR⁸,examples of such groups include piperidine, pyrrolidine, piperazine andmorpholine.

Conveniently one of R² or R³ is hydrogen and the other is C₁-C₈ alkylsubstituted by hydroxy and one or more methyl or ethyl groups. Moreconveniently one of R² or R³ is hydrogen and the other is CH(CH₃)CH₂OH,CH(Et)CH₂OH, C(CH₃)₂CH₂OH or CH(CH₂OH)₂. When one of R² or R³ ishydrogen and the other is CH(CH₃)CH₂OH or CH(Et)CH₂OH the resultingcompounds of formula (I) are particularly in the form of the (R) isomer.

Particular compounds of the formula I for use in the method of theinvention include those wherein R¹ represents a(2,3-difluorophenyl)methyl group and R² and R³ together represent a C₁₋₈alkyl group optionally substituted by one or more substituent groupsindependently selected from —OR⁴ wherein R⁴ represents hydrogen or aC₁₋₆ alkyl group.

Further particular compounds of the formula I include compounds of theformula Ia

wherein each R^(X) is independently selected from hydrogen, a C₁₋₄ alkylgroup optionally substituted by hydroxy, ammo, —O—C₁₋₄ alkyl, —S—C₁₋₄alkyl, —N—C₁₋₄ alkyl, —NHSO₂R, or —CONR₂ and provided that both R^(X)are not hydrogen or amino.

More particular compounds of the invention are wherein each R^(X) isindependently selected from hydrogen and hydroxymethyl, provided thatboth R^(X) are not hydrogen.

The invention also provides novel salts of the above compounds namelythe potassium salt of the compound wherein one R^(X) is hydrogen and theother is hydroxymethyl (cf. Example 2) and both the sodium and potassiumsalts of the compound wherein both R^(X) are hydroxymethyl (Examples 3and 4).

Compounds of the formula II are novel and represent a further aspect ofthe invention.

Preparation of a Compound of the Formula I Via Deprotection of aCompound of the formula II is novel and represents a further aspect ofthe invention.

Compounds of the formula III are novel and represent a further aspect ofthe invention.

Preparation of a Compound of the Formula Ii Via Reaction of a Compoundof the formula III with an amine of formula HNR₂R₃ is novel andrepresents a further aspect of the invention.

Compounds of the formula IV are novel (except for7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one)and represent a further aspect of the invention. They are convenientlyprepared by reaction of a compound of formula

with a reagent providing a leaving group L.

Such reaction represents a further independent aspect of this invention.

Compounds of the formula V are novel and represent a further aspect ofthe invention. They are conveniently prepared by reaction of a compoundof formula

with a halocarbonylsulfenylhalide. Convenient halogen atoms areindependently selected from chlorine and bromine, chlorine is apreferred halogen atom and chlorocarbonylsulfenylchloride is a preferredreagent.

Such reaction represents a further independent aspect of this invention.

Compounds of formula VI are novel and represent a further, independentaspect of the invention, they are conveniently prepared by reaction of acompound of formula

with a compound of formula L-R¹, wherein L is a leaving group and R¹ isas hereinbefore defined.

Such reaction is known for reaction of the compound of formula VII witha compound L-R¹ wherein L is bromine and R¹ is(2,3-difluorophenyl)methyl, this is disclosed in our WO-03/24966.

The compound of formula VII is conveniently provided as the monohydrate(cf. Example 1 (a)) and is commercially available, for example fromAldrich, Acros or Lancaster.

In a further aspect of the invention we provide the preparation of acompound of formula I from a compound of Formula V, via compounds ofFormula IV, III, II, using methods as set out hereinbefore.

In a further aspect of the invention we provide the preparation of acompound of formula I from a compound of Formula VI, via compounds ofFormula V, IV, III, II, using methods as set out hereinbefore.

In a further aspect of the invention we provide the preparation of acompound of formula I from a compound of Formula VII, via compounds ofFormula VI, V, IV, III, II, using methods as set out hereinbefore.

The invention will now be illustrated but not limited by the followingExamples:

EXAMPLE 15-[[(2,3-difluorolphenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one(a) 6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol

To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidinemonohydrate (67.7 g) in a mixture of water (920 ml) and tetrahydrofuran(300 ml) was added aqueous sodium hydroxide solution (46-48% w/w; 24 ml)followed by water (40 ml). The resulting hazy, pale yellow solution wascooled to 20° C. before adding 2,3-difluorobenzyl bromide (83.0 g)uniformly over 25 minutes, to yield a white precipitate. The mixture wasstirred at ambient temperature for 3.5 hours, the product collected andwashed twice with a mixture of water (68 ml) and tetrahydrofuran (24ml), to afford the title compound as a white solid (101.89 g).

¹H NMR: δ (DMSO-d6) 11.45 (1H, br.s), 7.44 (1H, t), 7.34 (1H, m), 7.15(1H, m), 6.58 (2H, br.s), 5.01 (1H, s), 4.39 (2H, s).

(b)7-amino-5-[[(2,3-dilnuorophenyl)methyl]thio][1,3]oxathiolo[5,4-d]pyrimidin-2-one

To a stirred suspension of6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol (9.58 g) intetrahydrofuran (96 ml) was added chlorocarbonylsulfenyl chloride (4.89g) over 7 minutes, followed by tetrahydrofuran (2 ml). The reactionmixture was stirred for 40 minutes and the resulting precipitatecollected by filtration, washing twice with tetrahydrofuran (19 ml), toafford the title compound as a pale yellow solid (11.31 g).

¹H NMR: δ (DMSO-d6) 7.89 (1H, br.s), 7.45 (1H, t), 7.34 (1H, m), 7.16(1H, m), 5.82 (1H, br.s), 4.39 (2H, s).

(c)7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one

To a stirred suspension of7-amino-5-[[(2,3-difluorophenyl)methyl]thio][1,3]oxathiolo[5,4-d]pyrimidin-2-one(5.03 g) and benzyltrimethylaimonium chloride (2.58 g) in acetonitrile(25 ml) at 50° C., was first added N,N-diethylaniline (2.46 g) followedby acetonitrile (5 ml), and then phosphorus oxychloride (7.41 g)followed by acetonitrile (5 ml). The reaction mixture was heated toreflux and maintained at this temperature for 36 hours, before coolingto ambient temperature and adding to water (25 ml) at 50° C. withstirring over 30 minutes. An additional acetonitrile (5 ml) rinse of thereaction vessel was added to the drown-out mixture, before heating to75° C. and slowly cooling to 25° C. at <0.5° C./min. The resultingmixture was held at 25° C. for 30 minutes and then collected byfiltration, washing four times with water (25 ml), to afford the titlecompound as an off-white solid (3.5 g).

¹H NMR: δ (DMSO-d6) 7.45 (1H, t), 7.38 (1H, m), 7.22 (1H, m), 4.50 (2H,s), 3.43 (1H, br.s).

(d)5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2-(3H)-one

(i) To a stirred suspension of7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one(5 g) and p-toluenesulfonic acid (29.4 mg) in toluene (40 ml) at 60° C.was added 3,4-dihydro-2H-pyran (1.83 g) over 1 hour. The reactionmixture was held at 60° C. for 2 hours and then cooled at 0.5° C./min toambient temperature. Saturated aqueous sodium bicarbonate solution (20ml) was first added to the reaction mixture, before stirring for 1 hour.The settled phases were separated and the organic solution furthertreated with saturated brine (20 ml). The brine phase was removed andtoluene (2 ml) added to the remaining organic phase to give a clearorange solution of7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2-(3H)-one.(44.5 ml).(ii) To a portion of the clear orange solution (10 ml) was addedtetrahydrofuran (5 ml), sodium carbonate (0.70 g) and (D)-alaninol (0.49g). The stirred reaction mixture was heated to 60° C. for 1.5 hours andthen further heated to 65° C. for 24 hours. Water (10 ml) was added tothe reaction mixture at 60° C. and stirring continued for 1 hour. Thesettled aqueous phase was removed and cyclohexane (15 ml) added to thestirred reaction mixture over 1 hour at 60° C., during which time theproduct crystallised. The resulting mixture was stirred at 60° C. for afurther 2 hours, cooled to ambient temperature at 0.25° C./min and thencooled to 0-5° C. The crystallised product was isolated, washed twicewith toluene (3 ml), to afford the title compound as an off-white solid(1.15 g).

¹H NMR: δ (DMSO-d6) 7.50 (1H, br.s), 7.41 (1H, t), 7.33 (1H, m), 7.15(1H, m), 5.54 (1H, d), 4.76 (1H, br.s), 4.44 (2H, s), 4.22 (1H, br.m),4.00 (1H, d), 3.56 (1H, m), 3.43 (1H, m), 3.34 (1H, m), 2.71 (1H, m),1.90 (1H, br.d), 1.62 (2H, br.d), 1.48 (2H, br.m), 1.10 (3H, d).

(e)5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2-(3H)-one

To a stirred solution of5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2-(3H)-one(10.0 g) in acetonitrile (200 ml), water (36 ml) and tetrahydrofuran (30ml) at 65° C. was added 1M hydrochloric acid (23.25 ml) over 3 hours.The product crystallised during the addition time. The mixture wascooled to 25° C. and the product collected by filtration, washingfirstly with water (30 ml) then acetonitrile (30 ml), to afford thetitle compound as an off-white solid (7.79 g).

¹H NMR: δ (DMSO-d6) 12.41 (1H, br.s), 7.35 (3H, m), 7.15 (1H, m), 4.73(1H, m), 4.40 (2H, m), 4.21 (1H, br.m), 3.44 (1H, m), 3.37 (1H, m), 1.09(3H, d).

EXAMPLE 25-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,potassium salt (a)5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one

To a stirred suspension of7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(31)-one(31.62 g), as prepared in Example 1 (c) above, in butyronitrile (150 ml)at room temperature was added diisopropylethylamine (16 ml, 1.0 eq),forming a solution. A butyronitrile line wash was applied (10 ml).Phenylvinylsulfone (20 g, 1.3 eq) was dissolved in butyronitrile (80 ml)in a separate flask and this solution was added to the vessel, followedby a line wash with butyronitrile (70 ml). The orange solution washeated to an internal temperature of 100° C. After 18 hours HPLC showedalmost complete consumption of the starting material (3.36%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-oneremained)*. At this point further diisopropylethylamine (16 ml, 1.0 eq)was added to the mixture at 50° C., followed by a small line wash ofbutyronitrile (5 ml). D-alaninol (9.25 mLs, 1.3 eq) was added, followedby a line wash of butyronitrile (5 ml). After 6.5 hrs HPLC showed almostcomplete conversion of the reaction intermediate (2.52%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2-(3H)-oneremained). The reaction was allowed to cool from 100 to 50° C. over 6.5hrs and held at 50° C. under nitrogen for 64 hrs. In order to get ahomogeneous sample the reaction was re-heated to 100° C. (1.19%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-onepresent by HPLC). The reaction was cooled from 100 to 50° C. over 1 hrand water (200 mLs) was added. A precipitate was observed. The mixturewas cooled from 50° C. to 20° C. over 2 hrs. The precipitate was ‘aged’at 20° C. for 1 hr and collected by filtration. The ‘cake’ was washedwith 1:1 water/butyronitrile (70 ml) twice, then with butyronitrile (35ml). The solid was then dried on the filter for 30 mins, collected anddried in a vacuum oven overnight at 50° C. A pale yellow solid5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-onewas obtained with 88% yield (44.33 g, HPLC area=98.75%).

¹H NMR: δ (DMSO-d6) 1.09 (d, 3H), 1.25 (m, 1H), 3.37 (dquin, 2H), 3.80(t, 2H), 4.13 (t, 2H), 4.20 (m, 1H), 4.39 (s, 2H), 4.75 (t, 1H), 7.15(m, 1H), 7.33 (m, 2H), 7.46 (d, 1H), 7.55 (t, 2H), 7.66 (t, 1H), 7.82(d, 2H).

(b) Isolation of Intermediate7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one

This may be achieved by following the process as outlined in (a) abovebut adding water to mixture at 50° C. (at point *). The mixture is thencooled to room temperature producing a precipitate which is isolated byfiltration.

¹H NMR: δ (DMSO-d6) 3.86 (t, 2H), 4.21 (t, 2H), 4.49 (s, 2H), 7.20 (m,1H), 7.37 (m, 2H), 7.55 (t, 2H), 7.65 (t, 1H), 7.83 (d, 2H).

(c) Preparation of5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,potassium salt

To a stirred suspension of5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one(2.0 g, 1.0 eq), as prepared in Example 2(a) above, in propan-2-ol (25.5ml) at room temperature under nitrogen, was added potassium t-butoxide(0.449, 1.05 eq). The resulting suspension was heated to an internaltemperature of 75-78° C. (reflux). After 1.5 hours at this temperature,water (4.5 ml) was added and the reaction became a solution. Thereaction was reheated to 75-78° C. before sampling for HPLC analysis.The sample showed almost complete consumption of the starting material(0.36%5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-oneremained). The reaction was allowed to cool, seeded at 50° C. with5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2-(3H)-one,potassium salt (2 mgs) and then cooled to room temperature. Theprecipitate was ‘aged’ at room temperature for 1 hour before filtering.The cake was washed with propan-2-ol (3×4 ml). The white solid wascollected and dried in a vacuum oven over night at 50° C. This processyielded 63% (0.96 g) of a white solid which was of high purity (99.65%by HPLC area).

¹H NMR: δ (DMSO-d6) 1.06 (d, 3H), 3.26-3.43 (m, 2H), 4.09 (quin, 1H),4.34 (m, 2H), 4.65 (bs, 1H), 5.59 (d, 1H), 7.12 (q, 1H), 7.28 (q, 1H),7.37 (t, 1H).

Alternatively, the compound of Example 1(e) may be reacted withpotassium hydroxide to give the title compound.

EXAMPLE 35-[[(2,3-difluorophenyl)methyl]thiol]-7-[[-2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,sodium salt (a)5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]-7-[(2,2,5-trimethyl-1,3-dioxan-5-yl)amino]thiazolo[4,5-d]pyrimidin-2(3H)-one

To a stirred suspension of7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one,prepared as shown in Example 1, steps (a) to (c), (1.0 g, 1.0 eq) inbutyronitrile (15 ml) at room temperature under nitrogen, was addeddiisopropylethylamine (0.5 ml, 1.0 eq), forming a solution.Phenylvinylsulfone (0.63 g, 1.3 eq) was added to the vessel. The orangesolution was heated to an internal temperature of 100° C. After 18 hoursHPLC showed almost complete consumption of the starting material (0.93%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-a]pyrimidin-2-(3H)-oneremained). At this point further diisopropylethylamine (0.5 ml, 1.0 eq)was added to the mixture at 50° C., followed by(2,2,5-trimethyl-1,3-dioxan-5-yl)amine (0.63 g, 1.5 eq).(2,2,5-trimethyl-1,3-dioxan-5-yl)amine is disclosed in J. Nat. Prod,1999, 62, 963-968.

After over night stir at 100° C. HPLC showed incomplete consumption ofthe reaction intermediate (32.56%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-oneremained). A further portion of (2,2,5-trimethyl-1,3-dioxan-5-yl)amine(0.21 g, 0.5 eq) was added. The reaction took another 4 days at 100° C.by which time the HPLC showed <10% of the intermediate (7.80%7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2-(3H)-one,as well as 13.42% of5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2(3H)-onewhere the acetonide had cleaved in situ). The reaction was allowed tocool from 100 to 50° C. Whilst at 50° C. water (10 ml) was added. Noprecipitate was observed. The layers were separated, organic layerwashed further with water (10 ml), dried over MgSO₄, filtered andevaporated to dryness to give an orange oil.

Purification was achieved by chromatography over silica eluting with20-30% ethyl acetate/ihexane on silica to yield a white solid.

¹H NMR: δ (DMSO-d6) 1.27 (s, 3H), 1.33 (s, 3H), 1.36 (s, 3H), 3.67 (d,2H), 3.82 (t, 2H), 4.14 (m, 4H), 4.38 (s, 2H), 7.20 (m, 2H), 7.34 (t,2H), 7.54 (t, 2H), 7.66 (t, 1H), 7.81 (d, 2H).

(b)5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2(3H)-one

5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]-7-[(2,2,5-trimethyl-1,3-dioxan-5-yl)amino]thiazolo[4,5-d]pyrimidin-2(3H)-one(0.19 g) was subjected to stirring under nitrogen with THF (2 ml), and1M HCl (2 ml). After an hour stirring at room temperature HPLC revealedthat the deprotection was complete (0.48% of the starting materialremaining).

To the mixture was added i-propyl acetate (5 ml) and water (2 ml). Thelower aqueous layer was removed and washed with a further two portionsof i-propyl acetate (2×7.5 ml). Combined organics were washed twice withwater (2×10 ml), dried over MgSO₄, filtered and evaporated to give awhite solid with 88% yield (0.156 g).

¹H NMR: δ (DMSO-d6) 1.25 (s, 3H), 3.60 (m, 4H), 3.80 (t, 2H), 4.15 (t,2H), 4.38 (s, 2H), 4.68 (t, 2H), 6.51 (s, 1H), 7.17 (m, 1H), 7.34 (t,2H), 7.57 (t, 2H), 7.67 (t, 1H), 7.84 (d, 2H).

(c)5-[[(2,3-difluorophenyl)methyl]thio]-7-[[-2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,sodium salt

To5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2(3H)-one(0.15 g, 1.0 eq) was added sodium t-butoxide (0.028 g, 1.1 eq). The twosolids were purged with nitrogen. Propan-2-ol (2 ml) was added to give asuspension at room temperature. The reaction was heated to give a yellowsolution. After 1 hour at reflux a sample was taken for HPLC analysis,which revealed completion (only 1.39% starting material remained). Thereaction was cooled to room temperature and a precipitate was observed.The product was filtered and washed with propan-2-ol (˜1 ml). Thecollected white solid was dried in a vacuum oven at 40° C. to yield 81%(0.091 g).

¹H NMR: δ (DMSO-d6) 1.22 (s, 3H), 3.40 (m, 2H), 3.56 (m, 2H), 4.35 (s,2H), 4.80 (s, 1H), 5.05 (t, 2H), 7.17 (m, 1H), 7.36 (t, 2H).

EXAMPLE 45-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,potassium salt

To5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-a]pyrimidin-2(3H)-one(0.881 g, 2.13 mmol) in methanol (20 ml) was added KOMe (0.165 g, 2.34mmol, 1.1 eq) and the mixture heated to reflux. Further methanol (10 ml)was added to obtain a solution. The solution was allowed to cool and thesolvent removed on a rotary evaporator and the resultant solid dried invacuo. This gave the title compound (0.828 g, 86%).

¹H NMR: δ (DMSO-d6) 1.25 (3H, s), 3.52 (2H, m), 3.62 (2H, m), 4.37 (2H,s), 4.8-5.2 (2H, broad s), 5.06 (1H, s), 7.15 (1H, m), 7.38 (2H, m)

Alternatively, the compound of Example 3(c) may be reacted withpotassium t-butoxide to give the title compound.

1. A method for the preparation of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof:

in which R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenylor C₂-C₆ alkynyl group, each of the groups being optionally substitutedby one or more substituent groups independently selected from halogenatoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R⁹ or an aryl or heteroaryl group, both of which maybe optionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl ortrifluoromethyl groups; R² and R³ each independently represent ahydrogen atom, or a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl group, the latter four groups may be optionallysubstituted by one or more substituent groups independently selectedfrom: (a) halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹; (b) a 3-8 membered ring optionallycontaining one or more atoms selected from O, S, NR⁸ and itselfoptionally substituted by C₁-C₃-alkyl or halogen; or (c) an aryl groupor heteroaryl group each of which may be optionally substituted by oneor more substituents independently selected from halogen atoms, cyano,nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl and trifluoromethyl groups; R⁴ represents hydrogen, C₁-C₆ alkyl ora phenyl group the latter two of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, phenyl, —OR¹¹ and —NR¹²R¹³ R⁵ and R⁶ independently represent ahydrogen atom or a C₁-C₆ alkyl or phenyl group the latter two of whichmay be optionally substituted by one or more substituent groupsindependently selected from halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocyclic ring system optionally containing afurther heteroatom selected from oxygen and nitrogen atoms, which ringsystem may be optionally substituted by one or more substituent groupsindependently selected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itselfoptionally substituted by one or more substituents independentlyselected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups; R¹⁰represents a hydrogen atom or a C₁-C₆-alkyl or a phenyl group, thelatter two of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁷ and —NR¹⁵R¹⁶; and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶,R¹⁷ independently represents a hydrogen atom or a C₁-C₆ alkyl, or aphenyl group; which method comprises contacting

wherein L is a leaving group with a thiazole nitrogen protecting groupreagent under appropriate reaction conditions to form a compound of theformula

wherein PG is a protecting group, reacting the compound of formula IIIwith an amine of formula HNR²R³ to form a compound of formula

and deprotection of the compound of formula II to give a compound of theformula I, and simultaneous or sequential conversion to apharmaceutically acceptable salt or solvate thereof.
 2. A method asclaimed in claim 1 and wherein R¹ represents an optionally substitutedbenzyl group.
 3. A method as claimed in claim 1 and wherein one of R² orR³ is hydrogen and the other is C₁-C₈ alkyl substituted by hydroxy andone or more methyl or ethyl groups.
 4. A method as claimed in claim 1for the preparation of compounds of the formula Ia

wherein each R^(X) is independently selected from hydrogen, a C₁₋₄ alkylgroup optionally substituted by hydroxy, amino, —O—C₁₋₄ alkyl,—S—C₁₋₄alkyl, —N—C₁₋₄ alkyl, —NHSO₂R, or —CONR₂ and provided that bothR^(X) are not hydrogen or amino.
 5. A method as claimed in claim 1wherein each R^(X) is independently selected from hydrogen andhydroxymethyl, provided that both R^(X) are not hydrogen.
 6. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof and wherein R¹represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, each of the groups being optionally substituted by one ormore substituent groups independently selected from halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹or an aryl or heteroaryl group, both of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethylgroups; R² and R³ each independently represent a hydrogen atom, or aC₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl group,the latter four groups may be optionally substituted by one or moresubstituent groups independently selected from: (a) halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹; (b) a 3-8 membered ring optionally containing one or moreatoms selected from O, S, NR⁸ and itself optionally substituted byC₁-C₃-alkyl or halogen; or (c) an aryl group or heteroaryl group each ofwhich may be optionally substituted by one or more substituentsindependently selected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶,—CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl andtrifluoromethyl groups; R⁴ represents hydrogen, C₁-C₆ alkyl or a phenylgroup the latter two of which may be optionally substituted by one ormore substituent groups independently selected from halogen atoms,phenyl, —OR¹¹ and —NR¹²R¹³ R⁵ and R⁶ independently represent a hydrogenatom or a C₁-C₆ alkyl or phenyl group the latter two of which may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶,—NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with thenitrogen atom to which they are attached form a 4- to 7-memberedsaturated heterocyclic ring system optionally containing a furtherheteroatom selected from oxygen and nitrogen atoms, which ring systemmay be optionally substituted by one or more substituent groupsindependently selected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itselfoptionally substituted by one or more substituents independentlyselected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups; R¹⁰represents a hydrogen atom or a C₁-C₆-alkyl or a phenyl group, thelatter two of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁷ and —NR¹⁵R¹⁶, each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ R¹⁵R¹⁶,R¹⁷ independently represents a hydrogen atom or a C₁-C₆ alkyl, or aphenyl group, and PG is a protecting group.
 7. A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof and wherein R¹represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, each of the groups being optionally substituted by one ormore substituent groups independently selected from halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹or an aryl or heteroaryl group, both of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethylgroups; R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl group the lattertwo of which may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, phenyl, —OR¹¹ and—NR¹²R¹³ R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆alkyl or phenyl group the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocyclicring system optionally containing a further heteroatom selected fromoxygen and nitrogen atoms, which ring system may be optionallysubstituted by one or more substituent groups independently selectedfrom phenyl, —OR¹⁴, —COOR¹⁴—NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶,NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself optionally substituted by one or moresubstituents independently selected from halogen atoms and —NR¹⁵R¹⁶ and—OR¹⁷ groups; R¹⁰ represents a hydrogen atom or a C₁-C₆-alkyl or aphenyl group, the latter two of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶, each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³,R¹⁴ R¹⁵, R¹⁶, R¹⁷ independently represents a hydrogen atom or a C₁-C₆alkyl, or a phenyl group; L is a leaving group; and PG is a protectinggroup.
 8. A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof and wherein R¹represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, each of the groups being optionally substituted by one ormore substituent groups independently selected from halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹or an aryl or heteroaryl group, both of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethylgroups; R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl group the lattertwo of which may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, phenyl, —OR¹¹ and—NR¹²R¹³ R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆alkyl or phenyl group the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶ NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocyclicring system optionally containing a further heteroatom selected fromoxygen and nitrogen atoms, which ring system may be optionallysubstituted by one or more substituent groups independently selectedfrom phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶ , —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself optionally substituted byone or more substituents independently selected from halogen atoms and—NR¹⁵R¹⁶ and —OR¹⁷ groups; R¹⁰ represents a hydrogen atom or aC₁-C₆-alkyl or a phenyl group, the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; each of R⁷, R⁸, R⁹, R¹¹,R¹², R¹³, R¹⁴ R¹⁵, R¹⁶, R¹⁷ independently represents a hydrogen atom ora C₁-C₆ alkyl, or a phenyl group; and L is a leaving group other thanchlorine.
 9. A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof and wherein R¹represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, each of the groups being optionally substituted by one ormore substituent groups independently selected from halogen atoms, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹or an aryl or heteroaryl group, both of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethylgroups; R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl group the lattertwo of which may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, phenyl, —OR¹¹ and—NR¹²R¹³ R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆alkyl or phenyl group the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocyclicring system optionally containing a further heteroatom selected fromoxygen and nitrogen atoms, which ring system may be optionallysubstituted by one or more substituent groups independently selectedfrom phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself optionally substituted byone or more substituents independently selected from halogen atoms and—NR¹⁵R¹⁶ and —OR¹⁷ groups; R¹⁰ represents a hydrogen atom or aC₁-C₆-alkyl or a phenyl group, the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; and each of R⁷, R⁸, R⁹,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ independently represents a hydrogenatom or a C₁-C₆ alkyl, or a phenyl group.
 10. A compound selected from5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,potassium salt;5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,sodium salt; and5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-2(3H)-one,potassium salt.